1. Field of the Invention
This invention is directed to pyranoindole derivatives, pharmaceutical compositions containing them, and to their use in the treatment of Hepatitis C viral infections, either alone or in conjunction with one or more biologically active agents, either concurrently or sequentially.
2. Related Background Art
Hepatitis C is a common viral infection that can lead to chronic Hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Infection with the Hepatitis C virus (HCV) leads to chronic Hepatitis in at least 85% of cases, is the leading reason for liver transplantation, and is responsible for at least 10,000 deaths annually in the United States (Hepatology, 1997, 26 (Suppl. 1), 2S–10S).
The Hepatitis C virus is a member of the Flaviviridae family, and the genome of HCV is a single-stranded linear RNA of positive sense (Hepatology, 1997, 26 (Suppl. 1), 11S–14S). HCV displays extensive genetic heterogeneity; at least 6 genotypes and more than 50 subtypes have been identified.
There is no effective vaccine to prevent HCV infection. The only therapy currently available is treatment with interferon-α (INF-α or combination therapy of INF-α with the nucleoside analog ribavirin (Antiviral Chemistry and Chemotherapy, 1997, 8, 281–301). However, only about 40% of treated patients develop a sustained response, so there is a need for more effective anti-HCV therapeutic agents.
The HCV genome contains a number of non-structural proteins: NS2, NS3, NS4A, NS4B, NS5A, and NS5B (J. General Virology, 2000, 81, 1631–1648). NS5B is an RNA-dependent RNA polymerase which is essential for viral replication, and therefore, the inhibition of NS5B is a suitable target for the development of therapeutic agents.
In the following U.S. patents, pyranoindole derivatives are disclosed and the compounds are stated to have antidepressant and antiulcer activity: U.S. Pat. No. 3,880,853 (Apr. 29, 1975), U.S. Pat. No. 4,118,394 (Oct. 3, 1978). In U.S. Pat. No. 4,179,503 (Dec. 18, 1979) pyranoindoles are disclosed and stated to have diuretic activity. In the following U.S. patents, pyranoindole derivatives are disclosed and the compounds are stated to have antiinflammatory, analgesic, antibacterial, and antifungal activity: U.S. Pat. No. 3,843,681 (Oct. 22, 1974), U.S. Pat. No. 3,939,178 (Feb. 17, 1976), U.S. Pat. No. 3,974,179 (Aug. 10, 1976), U.S. Pat. No. 4,070,371 (Jan. 24, 1979), U.S. Pat. No. 4,076,831 (Feb. 28, 1978). In the following U.S. patents, pyranoindole derivatives are disclosed and the compounds are stated to have antiinflammatory and analgesic activity: U.S. Pat. No. 4,670,462 (Jun. 2, 1987), U.S. Pat. No. 4,686,213 (Aug. 11, 1987), U.S. Pat. No. 4,785,015 (Nov. 15, 1988), U.S. Pat. No. 4,810,699 (Mar. 7, 1989), U.S. Pat. No. 4,822,781 (Apr. 18, 1989), U.S. Pat. No. 4,960,902 (Oct. 2, 1990). In U.S. Pat. No. 5,776,967 (Jul. 7, 1998) and U.S. Pat. No. 5,830,911 (Nov. 3, 1998), pyranoindole derivatives are disclosed and the compounds are said to inhibit cyclooxegenase-2 and be useful for treating arthritic disorders, colorectal cancer, and Alzheimer's disease.
Also, in the following U.S. patents, processes for preparing pyranoindole derivatives are disclosed: U.S. Pat. No. 4,012,417 (Mar. 15, 1977), U.S. Pat. No. 4,036,842 (Jul. 19, 1977), U.S. Pat. No. 4,585,877 (Apr. 29, 1986), U.S. Pat. No. 4,822,893 (Apr. 18, 1989). Processes for the resolution of racemic pyranoindole derivatives are disclosed in the following US Patents: U.S. Pat. No.: 4,501,899 (Feb. 26, 1985), U.S. Pat. No. 4,515,961 (May 7, 1985), U.S. Pat. No. 4,520,203 (May 28, 1985), U.S. Pat. No. 4,544,757 (Oct. 1, 1985).
Other aspects of the instant invention are described in applicant's U.S. provisional patent application No. 60/382,148, filed concurrently with the instant application, and which is hereby incorporated by reference in its entirety.